A striking feature of chronic fatigue syndrome (CFS) is its sudden onset in the majority of patients with a "flu-like" syndrome. However, despite an intensive search, a viral etiology has not been confirmed. The relationship of CFS to an antecedent infection also has been difficult to establish since most patients have been ill for years prior to evaluation, and the precipitating infection typically is self-reported, made in retrospect, and not documented. Thus, the role of viral precipitants, as well as early and perpetuating factors that might influence prognosis, are unknown. Moreover, it is likely that factors other than the infectious "trigger" contribute substantially to the development of chronicity. Although not specific to CFS, research has suggested that psychosocial factors may influence the severity and duration of infectious diseases. Questions remain whether they influence the illness course by affecting biological processes or illness behaviors (e.g., symptom reporting). Acute infectious mononucleosis (AIM), a common illness with significant morbidity, has clinical characteristics suited for the study of these questions. In the next 6-9 months, we will complete a NIMH-funded, prospective study of 200 individuals enrolled at the onset of AIM resulting from infection with EBV. We have collected a comprehensive battery of psychosocial measures (e.g., life events), simple, clinical measures of biological disease activity (e.g., transaminases, CBC), and serum and lymphocyte samples during the acute infection, and 1,2, and 6 months after illness onset. Surprisingly, 12% of subjects are not recovered at 6 months; our results suggest that both psychosocial and biological processes are involved. Using the stored lymphocyte/serum samples and a study visit specific to this Project to assess the development of perpetuators of illness, we will examine subjects who have and have not recovered from AIM to 1) assess the relationship between biological factors (e.g., EBV serology, EBV strain) and psychosocial factors (e.g., distress) in recovery from AIM; 2) identify illness perpetuators (e.g., altered sleep, cognition) and biological factors associated with non-recovery; 3) ascertain the characteristics of those in which biological and behavioral outcomes are discordant; and 4) characterize the post-infectious syndrome that develops following AIM and compare it to the CFS case definition. These Specific Aims will be accomplished by performing assays on stored specimens from each of the 5 (4 previous/1 new) study visits: EBV serology, EBV quantitative PCR, markers of persistent infection (EBNA-1, p21, ZEBRA), lymphocytes subsets (CD4, CD8, natural killers cells, activation markers), polymeric IgA, EBV stain, and skin testing for delayed hypersensitivity. These assays reflect characteristics of the host response and of EBV itself and, as such, will allow us to describe potential underlying mechanisms of non-recovery, as well as their interaction with psychosocial factors. Lastly, using factor analysis to derive an empirically-based criteria, we will examine how closely the post-infectious fatigue experienced by non-recovered individuals resembles CFS.